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Abstract

Exciting progress in the field of cancer immunotherapy has renewed the urgency of the need for basic studies of immunoregulation in both adaptive cell lineages and innate cell lineages. Here we found a central role for major histocompatibility complex (MHC) class I in controlling the phagocytic function of macrophages. Our results demonstrated that expression of the common MHC class I component β2-microglobulin (β2M) by cancer cells directly protected them from phagocytosis. We further showed that this protection was mediated by the inhibitory receptor LILRB1, whose expression was upregulated on the surface of macrophages, including tumor-associated macrophages. Disruption of either MHC class I or LILRB1 potentiated phagocytosis of tumor cells both in vitro and in vivo, which defines the MHC class I–LILRB1 signaling axis as an important regulator of the effector function of innate immune cells, a potential biomarker for therapeutic response to agents directed against the signal-regulatory protein CD47 and a potential target of anti-cancer immunotherapy.

Acknowledgements

We thank the members of the Weissman laboratory and the Stanford Stem Cell Center community for discussion and assistance; J.P. Volkmer, R. Majeti, K. Loh, N. Fernhoff, M. McCracken and J. Zee for input and advice; T. Storm, T. Naik, A. McCarty, F. Khameneh, J. Ho and P. Lovelace for logistical support; and G. Krampitz (Stanford University) for the APL1 cell line. Supported by the D.K. Ludwig Fund for Cancer Research (NIH R01CA086017 and NIHG R01GM100315 to I.L.W.), the Cancer Research Institute (Irvington Fellowship to R.L.M.), the Human Frontier Science Program Organization (postdoctoral fellowship to B.R.), the NIH (hematology training grant T32 HL120824-03 to B.R.), the University of Wisconsin Medical Scientists Training Program (GM008692 to L.J.B.), the National Research Service Award 1F30DK108561, the Paul and Daisy Soros Fellowship for New Americans (to J.M.T.) and the Stanford Medical Scientist Training Program (NIH GM07365 to A.A.B., K.W., A.M.R., J.M.T., B.M.G. and J.Y.C.).

Competing interests

K.W., A.M.R., I.L.W. and R.L.M. and are co-inventors on patent application PCT/US2015/057233, which is related to this work, and own stock of FortySeven, which is pursing clinical approval of antibody Hu5F9-G4, directed against human CD47.